Due to the emerging threat of epidemic and pandemic influenza, it is increasingly important to initiate informative studies that dissect the coordinated immune response to influenza virus infections. While much is known about the important role adaptive immune cells play in viral clearance and protection to subsequent infections, much less is understood about innate immunity and in particular, the contributions of DC and NK cells. Therefore our long-term goals are to understand how these innate cells control viral load and regulate immunity to influenza virus infections therein regulating the extent of disease and the eventual outcome for the host. Our preliminary results show that NK cells and DC are integral to proper control of influenza virus infections in that NK cell accumulation is distinct in lethal and sublethal influenza virus infection, NK depleted mice show enhanced influenza-associated morbidity, mortality and antigen load, and DC regulate the influenza-specific CD8 T cell response both in the lymph nodes and lungs to allow recovery from infection. Therefore in this collaborative proposal we will combine our expertise in NK cells, DC, and influenza-specific immune responses and utilize our mouse model of influenza virus infection to determine how NK cells and DC control influenza virus infections in the following Specific Aims 1) Determination of the mechanism of pulmonary DC mediated enhancement of the influenza-specific CD8 T cell response, 2) Determination of the extent and mechanism of NK cell-mediated protection against early death during influenza infection-NK control of peak viral load and infection of respiratory DC (rDC). The knowledge gained from this study will not only be relevant to our understanding of the important early and underlying events required for effective immune responses and control of influenza-virus infections but also in the design of strategies to combat epidemic and pandemic influenza and other respiratory virus infections. [unreadable] [unreadable] [unreadable]